Human .alpha..sub.1 -antitrypsin (AAT) is a monomer with a molecular weight of about 52 Kd. Normal AAT contains 394 residues, with three complex oligosaccharide units exposed to the surface of the molecule, linked to asparagines 46, 83, and 247 (Carrell, et al., Nature 298:329 (1982).
AAT is the major plasma proteinase inhibitor whose primary function is to control the proteolytic activity of trypsin, elastase, and chymotrypsin in plasma. In particular, the protein is a potent inhibitor of neutrophile elastase, and a deficiency of AAT has been observed in a number of patients with chronic emphysema of the lungs. A proportion of individuals with serum deficiency of AAT may progress to cirrhosis and liver failure (e.g., Wu, et al., BioEssays 13(4):163 (1991).
Because of the key role of AAT as an elastase inhibitor, and because of the prevalence of genetic diseases resulting in deficient serum levels of AAT, there has been an active interest in recombinant synthesis of AAT, for human therapeutic use. To date, this approach has not been satisfactory for AAT produced by microbial recombinant methods, because of a short effective serum halflife of the recombinant protein. Methods for making AAT using mammalian cell culture or transgenic animals, while expected to produce a more active AAT, by virtue of a more human glycosylation pattern, are relatively expensive, and to date, have limited the available supply of glycosylated AAT.
It would therefore be useful to provide a method for inexpensive production of glycosylated, therapeutically effective AAT.